Celiac disease, also known as celiac sprue, is a inflammatory disease affecting the small intestine that results from an immunological reaction to dietary glutens. Celiac affects up to 1% of the population, and is managed only by a strict gluten-free diet. The disease is strongly associated with MHO class II molecules and their presentation of antigenic peptides derived from gluten to CD4+ T cells. In celiac disease, over 90% of patients express the DQ2 allele (DQA1*0501/DQB1*0201). Enzymatic degradation of gluten generates proline and glutamine rich peptides that have epitopes that recognize DQ2 and are recognized by intestinal DQ2-restricted T cells in celiac patients. The therapeutic strategy proposed here is to inhibit the immune response to dietary gluten by blockade of the MHC class II HLA-DQ2 binding site with a small molecule peptide mimetic, preventing antigen binding and recognition. A potent antigenic peptide, QLQPFPQPELPY (gliaden alpha-l) has been crystallized in DQ2, and this structure forms the basis for drug design of prototype inhibitors. The first specific aim is to establish a competition binding assay and to synthesize and evaluate binding of prototype ligands designed by N- and C-terminal truncation and side chain variants to define structure-activity relationships (SAR) and to determine a minimal active sequence. The second specific aim is to optimize a lead series using the prototype SAR and biostructural data to design peptide analogs and mimetics that fully occupy key binding pockets, make critical backbone interactions, and are modified to avoid T cell recognition. The resulting ligands will make it feasible in future work to determine if the optimized analogs can inhibit a gliadin stimulated, DQ2-restricted T -cell response in a cellular model. Candidate analogs would be further optimized for enhanced potency in the cellular model and reduced susceptibility to digestive enzymes. [unreadable] [unreadable]